Abstract Daily exercise is a low-cost treatment that improves metabolic health and protects against age-related diseases. However, many people are unable to perform an endurance exercise regimen due to illness, disability, advanced age or a work schedule that enforces sedentary behavior. Furthermore, humans have wide individual differences in their response to exercise. The genetic factors that cause this variance are not well understood. Here, we propose to use the fruit fly genetic model system to identify the causes of this variance. In the process, we will identify novel targets for therapeutic pharmaceuticals that can mimic the benefits of exercise in patients that are unable to complete an exercise program. Preliminary data strongly shows that activation of octopaminergic neurons during exercise is critical for inducing metabolic adaptations in muscle and fat. Furthermore, treatment with octopamine is capable of inducing exercise adaptations in sedentary flies. Here, we will identify which receptor or receptors are required for octopamine signaling to induce these benefits (Aim 1). Secondly, we will take advantage of sex-specific differences in exercise response in flies to identify the genetic differences that cause individual variation in response to daily exercise. These results will 1) inform the development of diagnostics to predict individual responses to exercise training, and 2) provide novel targets for therapeutics to provide the benefits of exercise to sedentary patients.